Diastolic Dysfunction as a Positive Predictor of Recurrent Vascular Events in Patients With Noncardioembolic Stroke.

BACKGROUND: This study aimed to assess the effects of left ventricular diastolic dysfunction (LVDD) on vascular outcomes among patients with stroke of noncardioembolic origins. METHODS: This prospective observational study enrolled 563 patients with noncardioembolic stroke (mean age, 67.9 years; 66.7% men and 33.3% women individuals) registered in the Tokyo Women's Medical University Stroke Registry between 2013 and 2020. Then, patients were divided into the LVDD and non-LVDD groups. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death 1 year after stroke onset. The effect of LVDD on vascular events was assessed using multivariable Cox regression analyses. RESULTS: A total of 130 (23.1%) patients had any grade of LVDD, and patients with LVDD had a higher risk of major adverse cardiovascular event at 1 year than those without LVDD (annual rate, 20.9% versus 10.8%; log-rank P=0.001). The multivariable Cox proportional hazards regression model demonstrated that the presence of LVDD was independently associated with the major adverse cardiovascular event risk (hazard ratio, 1.79 [95% CI, 1.02-3.12]; P=0.019). Furthermore, the LVDD grade was proportional to the risk of major adverse cardiovascular events and recurrent stroke. CONCLUSIONS: LVDD may be associated with further vascular events after a noncardioembolic stroke, suggesting the importance of LVDD evaluations in risk stratification and secondary prevention in patients with noncardioembolic stroke. REGISTRATION: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Association of circulating CD34+ cells level and prognosis after ischemic stroke.

BACKGROUND: CD34 is a transmembrane phosphoglycoprotein and a marker of hematopoietic and nonhematopoietic stem/progenitor cells. In experimental studies, CD34+ cells are rich sources of endothelial progenitor cells and can promote neovascularization and endothelial repair. The potential role of CD34+ cells in stroke patients remains unclear. AIMS: We aimed to assess the prognostic effect of circulating CD34+ cell levels on the risk of vascular events and functional prognosis in stroke patients. PATIENTS AND METHODS: In this prospective observational study, patients with ischemic stroke were consecutively enrolled within 1 week of onset and followed up for 1 year. Patients were divided into three groups according to tertiles of the level of circulating CD34+ cells (Tertile 1, <0.51/µL; Tertile 2, 0.51-0.96/µL; and Tertile 3, >0.96/µL). The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. The secondary outcomes included the modified Rankin scale (mRS) scores. RESULTS: A total of 524 patients (mean age, 71.3 years; male, 60.1%) were included. High CD34+ cell levels were associated with younger age (p < 0.001) and low National Institutes of Health Stroke Scale scores at admission (p = 0.010). No significant differences were found in the risk of MACEs among the three groups (annual rates: 15.0%, 13.4%, and 12.6% in Tertiles 1, 2, and 3, respectively; log-rank p = 0.70). However, there were significant differences in the mRS scores at 3 months (median (interquartile range); 2 (1-4), 1 (1-3), and 1 (0-2) in Tertiles 1, 2, and 3, respectively; p = 0.010) and 1 year (3 (1-4), 2 (1-4), and 1 (0-3); p < 0.001) among these groups. After multivariable adjustments, a higher CD34+ cell level was independently associated with good functional outcomes (mRS score of 0-2) at 3 months (adjusted odds ratio (OR), 1.43; 95% confidence interval (CI), 1.01-2.05) and 1 year (adjusted OR, 1.53; 95% CI, 1.09-2.16). CONCLUSION: Although no correlations were found between circulating CD34+ cell levels and vascular event risk, elevated CD34+ cell levels were associated with favorable functional recovery in stroke patients. DATA ACCESS STATEMENT: Data supporting the findings of this study are available from the corresponding author on reasonable request. CLINICAL TRIAL REGISTRATION: The TWMU Stroke Registry is registered at https://upload.umin.ac.jp as UMIN000031913.

Association of Age-Related Spontaneous Internal Jugular Vein Reflux with Cognitive Impairment and Incident Dementia.

BACKGROUND: It remains unclear whether changes in the venous circulation contribute to cognitive decline. OBJECTIVE: This study aimed to clarify whether the spontaneous jugular vein reflux (JVR) is associated with cognitive impairment and incident dementia. METHODS: Patients with any evidence of cerebral vessel disease on magnetic resonance imaging (MRI) were consecutively enrolled between October 2015 to July 2019. We employed carotid duplex sonography to measure the internal jugular vein (IJV). The subjects were classified into two groups based on the degree of JVR on either side: none, mild (JVR(-) group) and moderate, severe (JVR (+) group) JVR. They underwent both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese (MoCA-J) global tests. Their cognitive status was prospectively assessed until March 2023. RESULTS: 302 patients with an MMSE score ≥24 underwent duplex sonography of the IJV. Among them, 91 had spontaneous JVR on either side. Both MMSE and MoCA-J were significantly lower in patients with JVR (+) group than in the JVR (-) group. After the adjustment for risk factors and MRI findings, intergroup differences in MoCA-J remained significant. Among the cognitive subdomains, median executive function and memory scores were significantly lower in the JVR (+) group than in the JVR (-) group. During the median 5.2-year follow-up, 11 patients with incident dementia were diagnosed. Patients with severe JVR were significantly more likely to be diagnosed with dementia (log-rank test, p = 0.031). CONCLUSIONS: Spontaneous IJV reflux especially severe JVR, was associated with global cognitive function, and potentially with incident dementia.

Association between total cerebral small vessel disease score and cognitive function in patients with vascular risk factors.

Hypertension is the most important risk factor for cerebral small vessel disease (SVD). In this cross-sectional study, we tested the independent association of cerebral SVD burden with global cognitive function and each cognitive domain in patients with vascular risk factors. The Tokyo Women's Medical University Cerebral Vessel Disease (TWMU CVD) registry is an ongoing prospective, observational registry in which patients with any evidence of CVD in magnetic resonance imaging (MRI) and at least one vascular risk factor were consecutively enrolled. For SVD-related findings, we evaluated white matter hyperintensity, lacunar infarction, cerebral microbleeds, enlarged perivascular space, and medial temporal atrophy. We used the total SVD score as the SVD burden. They underwent the Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests, and each cognitive domain was evaluated. After excluding patients without MRI T2* images and those with MMSE score <24, we analyzed 648 patients. The total SVD score was significantly associated with MMSE and MoCA-J scores. After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and MoCA-J score remained significant. The total SVD score was independently associated with attention. In conclusion, the total SVD score, cerebral SVD burden, was independently association with global cognitive function and attention. A strategy to reduce SVD burden will have the potential to prevent cognitive decline. A total of 648 patients with any evidence of cerebral small vessel disease (SVD) in MRI and at least one vascular risk factor underwent Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests. The total SVD scores count the presence of each SVD-related findings (white matter hyperintensity, Lacunar infarction, cerebral microbleeds and enlarged perivascular space), ranging from 0 to 4, as the SVD burden. Total SVD scores were significantly associated with MoCA-J scores (r = -0.203, P < 0.001). After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and global cognitive scores remained significant.

Hyperhomocysteinemia Increases Vascular Risk in Stroke Patients with Chronic Kidney Disease.

AIMS: We aimed to assess the prognostic impact of hyperhomocysteinemia (HHcy) on the recurrent vascular event risk in stroke patients with or without chronic kidney disease (CKD). METHODS: In this prospective observational study, 621 patients (mean age, 69.5 years; male, 62.2%) with ischemic stroke or transient ischemic attack were consecutively enrolled within 1 week of onset and followed-up for 1 year. HHcy was defined as elevated levels of fasting total homocysteine ＞15 µmol/L. CKD was defined as an estimated glomerular filtration rate of ＜60 mL/min/1.73 m2 or a history of renal replacement therapy. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. RESULTS: The prevalence of HHcy was 18.5%. Patients with HHcy were more likely to have intracranial (37.4% versus 24.8%; p=0.008) and extracranial (20.9% versus 13.0%; p=0.037) artery stenosis than were those without HHcy. At 1 year, patients with HHcy were at a greater risk of MACE than were those without HHcy (annual rate, 17.8% versus 10.4%; log-rank p=0.033). In the Cox proportional hazard regression models, HHcy was independently associated with an increased risk of MACE in patients with CKD (adjusted hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.02-4.20), whereas HHcy was not predictive of MACE in those without CKD (adjusted HR, 1.00; 95% CI, 0.30-3.32). CONCLUSIONS: Elevated levels of serum homocysteine can be an important modifiable risk factor in stroke patients with CKD, but not in those without CKD.

Long-Term Outcome in Patients With Acute Ischemic Stroke and Heart Failure.

BACKGROUND: This study aimed to identify the association between long term functional outcomes and acute ischemic stroke (AIS) in patients with heart failure (HF) in Japan and whether 1-year event risks can be related to these patients.Methods and Results: This was a prospective observational study, and 651 patients registered in the Tokyo Women's Medical University Stroke Registry were classified into the HF and non-HF groups. Functional outcome at 1 year after stroke onset was defined as either good (modified Rankin Scale [mRS] score of 0-2) or poor (mRS score of 3-6). The primary outcome was a composite of major adverse cardiovascular events (MACE), including non-fatal stroke, non-fatal acute coronary syndrome, and vascular death. Patients with HF had a higher poor functional outcome rate at 1 year than those without HF (54.7% vs. 28.2%, P<0.001). Multivariate logistic regression analysis also demonstrated the prevalence of HF was an independent predictor of an mRS score of ≥3 at 1 year after stroke onset (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; P=0.036). Furthermore, patients with HF tended to have a higher risk of MACE and all-cause mortality than those without HF. CONCLUSIONS: AIS patients with HF were associated with poor functional outcome at the 1-year follow up. Further multicenter studies involving a larger number of patients are warranted to verify these results.

Reclassification and risk stratification of embolic stroke of undetermined source by ASCOD phenotyping.

BACKGROUND: Common vascular diseases underlying stroke, including atherosclerosis, small-vessel disease (SVD), and cardioembolic pathology, can be present in patients with embolic stroke of undetermined source (ESUS), although these are not direct causes of stroke. AIMS: To describe the frequency and degree of the three major diseases using atherosclerosis, SVD, cardiac pathology, other causes, and dissection (ASCOD) phenotyping and to assess their prognostic implications in ESUS. METHODS: In this prospective observational study, 221 patients with ESUS within 1 week of onset were consecutively enrolled and followed up for 1 year. Vascular diseases associated with stroke were assessed using the ASCOD classification. The primary outcome was a composite of nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: Among 221 patients (mean age, 69.6 years; male, 59.7%), 135 (61.1%), 102 (46.2%), and 107 (48.4%) had any grade of atherosclerosis (A2 or A3), SVD (S3), and cardiac pathology (C2 or C3), respectively. ESUS patients graded as A2 or A3 (i.e. ipsilateral atherosclerotic plaque, contralateral ⩾ 50% stenosis, or aortic arch plaque) were at a significantly higher risk of composite vascular events than those graded as A0 (i.e. no atherosclerotic disease) (adjusted hazard ratio (95% confidence interval), 2.40 (1.01-5.72). No differences were observed in the event risk between patients with S3 (i.e. magnetic resonance imaging evidence of SVD) and S0 (i.e. no SVD) and between those with C2 or C3 (i.e. presence of any cardiac pathology) and C0 (i.e. no cardiac abnormalities). CONCLUSIONS: Atherosclerotic diseases corresponding to ASCOD grade A2 or A3 were predictive of recurrent vascular events in ESUS patients. Reclassification of ESUS using ASCOD phenotyping provides important clues for risk prediction and may guide optimal management strategies.

Remote Ischemic Conditioning Enhances Collateral Circulation Through Leptomeningeal Anastomosis and Diminishes Early Ischemic Lesions and Infarct Volume in Middle Cerebral Artery Occlusion.

Remote ischemic conditioning (RIC) has attracted much attention as a protective strategy for the heart and brain, although the underlying mechanisms remain unclear. We hypothesized that RIC enhances collateral circulation during cerebral ischemia through endothelial function and mitigates both early ischemic change and final infarct volume. We tested the RIC and sham procedure 30 min after permanent middle cerebral artery occlusion (MCAO) in male mice. Collateral circulation was examined during the procedure with 2D color-coded ultrasound imaging. Immediately after four cycles of RIC, early ischemic lesions on magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and development of pial collateral vessels were examined. The neurological signs and infarct volume with TTC were examined until 48 h after daily RIC. As compared with sham procedure, RIC enhanced collateral circulation, diminished early ischemic lesions, enlarged pial collaterals, and mitigated infarct volume. Next, we examined the effect of inhibitor of nitric oxide synthase (NOS) and Akt on the beneficial effect of RIC in MCAO. Both allosteric Akt inhibitor, 8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK2206), and two NOS inhibitors, N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), counteracted the beneficial effect of RIC on collateral circulation, early lesions, pial anastomosis, and infarct volume. In permanent MCAO, RIC could enhance collateral circulation through leptomeningeal anastomosis with Akt-eNOS pathway and diminish early lesion and final infarct volume.

Triglyceride-glucose index as a prognostic marker after ischemic stroke or transient ischemic attack: a prospective observational study.

BACKGROUND: Triglyceride-glucose (TyG) index has been proposed as a simple and credible surrogate for insulin resistance and an independent predictor of cardiovascular outcomes. Due to lack of data on TyG index in stroke, we aimed to evaluate the predictive value of the index for recurrent vascular event risk among stroke patients. METHODS: This was a prospective observational study, in which 866 patients (mean age, 70.1 years; male, 60.9%) with ischemic stroke (n = 781) or transient ischemic attack (n = 85) within 1 week of onset were consecutively enrolled and followed up for 1 year. The TyG index was calculated as ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Patients were divided into 3 groups according to the tertile of TyG index levels: tertile 1, < 8.48; tertile 2, 8.48-9.01; and tertile 3, > 9.01. The primary outcome was a composite of major adverse cardiovascular events (MACE), including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The median TyG index was 8.74 (interquartile range, 8.34-9.16). Higher levels of TyG index were significantly associated with increased prevalence of ipsilateral extracranial carotid (P = 0.032) and intracranial (P = 0.003) atherosclerotic stenosis. There were significant differences in the MACE risk between the three groups (annual rate, 8.6%, 11.6%, and 17.3% in the tertile 1, tertile 2, tertile 3 groups, respectively; log-rank P = 0.005). After multivariable adjustments, the TyG index remains to be a significant predictor of MACE, with an adjusted hazard ratio for tertile 3 versus tertile 1 groups (95% confidence interval) of 2.01 (1.16-3.47). Similar results were also found for the risk of recurrent stroke. CONCLUSIONS: TyG index is associated with cervicocerebral atherosclerosis and the MACE risk after a stroke, suggesting the potential value of TyG index to optimize the risk stratification of stroke patients. Trial registration URL:  https://upload.umin.ac.jp . Unique identifier: UMIN000031913.

Remote ischemic conditioning for acute ischemic stroke part 2: Study protocol for a randomized controlled trial.

Background: Remote ischemic conditioning (RIC) refers to the application of repeated short periods of ischemia intended to protect remote areas against tissue damage during and after prolonged ischemia. Aim: We aim to evaluate the efficacy of RIC, determined by the modified Rankin Scale (mRS) score at 90 days after stroke onset. Design and methods: This study is an investigator-initiated, multicenter, prospective, randomized, open-label, parallel-group clinical trial. The sample size is 400, comprising 200 patients who will receive RIC and 200 controls. The patients will be divided into three groups according to their National Institutes of Health Stroke Scale score at enrollment: 5-9, mild; 10-14, moderate; 15-20, severe. The RIC protocol will be comprised of four cycles, each consisting of 5 min of blood pressure cuff inflation (at 200 mmHg or 50 mmHg above the systolic blood pressure) followed by 5 min of reperfusion, with the cuff placed on the thigh on the unaffected side. The control group will only undergo blood pressure measurements before and after the intervention period. This trial is registered with the UMIN Clinical Trial Registry (https://www.umin.ac.jp/: UMIN000046225). Study outcome: The primary outcome will be a good functional outcome as determined by the mRS score at 90 days after stroke onset, with a target mRS score of 0-1 in the mild group, 0-2 in the moderate group, and 0-3 in the severe group. Discussion: This trial may help determine whether RIC should be recommended as a routine clinical strategy for patients with ischemic stroke.

[A case of cardioembloic stroke with wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome].

Here, we report a case of an 85-year-old man who presented sudden onset of diplopia, dysarthria, and gait disturbance. On admission, he exhibited bilateral adduction palsy, convergence palsy, and binocular exotropia in the forward gaze showing wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome. He had a history of chronic nonvalvular atrial fibrillation. DWI-MRI revealed acute ischemic lesions in the paramedian pontine tegmentum, lower midbrain, both cerebellar hemispheres, and left frontal cortex. He was thus diagnosed with an acute phase of cardioembolic stroke. Subsequently, the right eye adduction palsy in the forward gaze was slightly improved, but other eye movement disorders persisted during discharge from the hospital. The pathology was suspected to involve bilateral damages to both medial longitudinal fasciculus and the paramedian pontine reticular formation. WEBINO syndrome was not only ascribed to lacunar infarction and large artery atherosclerosis but also cardioembolic stroke. The presence of other non-eye symptoms and multiple ischemic lesions could be the characteristics of WEBINO syndrome following cardioembolic stroke.

Prognostic Role of Hypertriglyceridemia in Patients With Stroke of Atherothrombotic Origin.

BACKGROUND AND OBJECTIVES: Hypertriglyceridemia is perceived to promote atherosclerotic pathology, but its role in stroke has not been well defined. Our aim was to assess the contribution of hypertriglyceridemia to residual vascular risk in patients with atherothrombotic stroke. METHODS: The Tokyo Women's Medical University Stroke Registry is an ongoing prospective, observational registry in which 870 patients with acute ischemic stroke or TIA within 1 week of onset were consecutively enrolled and followed up for 1 year. Hypertriglyceridemia was defined as serum triglycerides levels of ≥150 mg/dL under fasting conditions. Significant stenosis of the cervicocephalic arteries was defined as having ≥50% stenosis or occlusion. The primary outcome was major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: Of 870 patients (mean age 70.1 years, male 60.9%), 217 (24.9%) had hypertriglyceridemia. High triglycerides levels were significantly associated with an increased prevalence of intracranial artery stenosis, particularly in the anterior circulation, rather than extracranial artery stenosis. Patients with hypertriglyceridemia had a greater risk of major adverse cardiovascular events than those without (annual rate 20.9% vs 9.7%; p < 0.001), even after adjustment for potential confounders, including baseline low-density lipoprotein cholesterol and statin use (adjusted hazard ratio 2.46, 95% CI 1.62-3.74). The higher risk of vascular events in patients with hypertriglyceridemia vs without hypertriglyceridemia was observed among patients with stroke of atherothrombotic origin (n = 174, annual rate 35.1% vs 14.2%; p = 0.001), those with significant intracranial artery stenosis (n = 247, annual rate 29.9% vs 14.7%; p = 0.006), and those with significant extracranial carotid artery stenosis (n = 123, annual rate 23.0% vs 9.4%; p = 0.042). In contrast, hypertriglyceridemia was not predictive of recurrent vascular events in patients with cardioembolic stroke (n = 221, annual rate 19.1% vs 10.5%; p = 0.18). DISCUSSION: Hypertriglyceridemia is an important modifiable risk factor that drives residual vascular risk in patients with stroke of atherothrombotic origin, even while on statin therapy. TRIAL REGISTRATION INFORMATION: UMIN000031913 at upload.umin.ac.jp. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with atherothrombotic stroke, hypertriglyceridemia is associated with an increased risk of major cardiovascular events.

Atherogenic Dyslipidemia and Residual Vascular Risk After Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Notwithstanding the current guideline-based management, patients with stroke retain a substantial risk of further vascular events. We aimed to assess the contribution of atherogenic dyslipidemia (AD) to this residual risk. METHODS: This was a prospective observational study, in which 792 patients (mean age, 70.1 years; male, 60.2%) with acute ischemic stroke (n=710) or transient ischemic attack (n=82) within 1 week of onset were consecutively enrolled and followed for 1 year. AD was defined as having both elevated levels of triglycerides ≥150 mg/dL and low HDL-C (high-density lipoprotein cholesterol) <40 mg/dL in men or <50 mg/dL in women, under fasting conditions. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The prevalence of AD was 12.2%. Patients with AD more often had intracranial artery stenosis than those without (42.3% versus 24.1%; P=0.004), whereas no differences were observed in the prevalence of extracranial artery stenosis (17.7% versus 12.9%; P=0.62) or aortic plaques (33.3% versus 27.0%; P=0.87). At 1 year, patients with AD were at a greater risk of major adverse cardiovascular events (annual rate, 24.5% versus 10.6%; hazard ratio [95% CI], 2.33 [1.44-3.80]) and ischemic stroke (annual rate, 16.8% versus 8.6%; hazard ratio [95% CI], 1.84 [1.04-3.26]) than those without AD. When patients were stratified according to baseline LDL-C (low-density lipoprotein cholesterol) level, AD was predictive of major adverse cardiovascular events among those with LDL-C ≥100 mg/dL (n=509; annual rate, 20.5% versus 9.6%; P=0.036) as well as those with LDL-C <100 mg/dL (n=283; annual rate, 38.6% versus 12.4%; P<0.001). CONCLUSIONS: AD is associated with intracranial artery atherosclerosis and a high residual vascular risk after a stroke or transient ischemic attack. AD should be a promising modifiable target for secondary stroke prevention. Registration: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Effects of Pemafibrate in Patients with Stroke and Hypertriglyceridemia: Baseline Cerebral Artery Diseases and 3-Month Laboratory Outcomes.

AIMS: The role of hypertriglyceridemia in stroke is poorly understood. The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study was designed to assess the effects of a novel selective peroxisome proliferator-activated receptor alpha modulator, pemafibrate, on vascular outcomes in stroke patients with hypertriglyceridemia. METHODS: This was a prospective single-arm study including 74 patients (mean age, 64.1 years; male 75.7%) with stroke and hypertriglyceridemia (defined as fasting serum triglycerides levels of ≥ 150 mg/dL) who were treated with pemafibrate at 0.2 mg or 0.1 mg/day. The present report assessed the association of hypertriglyceridemia with cerebral large and small vessel diseases at baseline and changes in laboratory parameters after a three-month pemafibrate therapy. RESULTS: Patients with triglycerides levels of ≥ 227 mg/dL (higher than the median) more often presented with intracranial artery atherosclerotic stenosis than those with triglycerides levels of 150-227 mg/dL (44.4% vs. 21.6%, p=0.037). On the other hand, no differences were found in the prevalence of extracranial artery atherosclerosis and cerebral small vessel diseases. Mean triglycerides levels were significantly reduced from 285 mg/dL at baseline to 175 mg/dL at 3 months (p＜0.001). High-density lipoprotein cholesterol levels increased from 48 mg/dL to 53 mg/dL (p＜0.001). In addition, significant reductions in alanine aminotransferase, γ-glutamyl transpeptidase, and interleukin-6 levels were observed (p＜0.001, p=0.002, and p=0.044, respectively). CONCLUSIONS: Higher triglycerides levels are associated with intracranial artery atherosclerosis. Pemafibrate showed pleiotropic effects not only in ameliorating atherogenic dyslipidemia but also in the reduction of the levels of inflammatory markers and hepatobiliary enzymes.

Localization of Infratentorial Lesion could Predict Patent Foramen Ovale as an Etiology in Embolic Stroke of Undetermined Source.

AIM: Embolic stroke of undetermined source (ESUS) is a clinical construct introduced to describe cryptogenic stroke cases with ambiguous diagnoses. Cardiac causes are recognized as a major cause of ESUS, Patent foramen ovale (PFO) being among them. We aimed to investigate the relationship between infarct patterns and PFO in patients with ESUS. METHODS: We evaluated 190 consecutive patients with ESUS registered in the Tokyo Women's Medical University Stroke Registry. Among them, 94 patients who underwent magnetic resonance imaging and angiography, as well as transthoracic and transesophageal echocardiography, were included in this study. The infarct patterns were classified according to location (infratentorial or non-infratentorial lesions), size (small or large infarcts), and number (single or multiple lesions). RESULTS: Prevalence of PFO was significantly higher in patients in the infratentorial than those in the non-infratentorial lesion group (40.7% versus 14.9%, respectively; P=0.007). However, neither lesion size nor number were associated with PFO. In multivariate logistic regression analysis, the presence of infratentorial lesions was independently associated with PFO in ESUS patients (odds ratio: 2.18; 95% confidence interval: 1.24-3.95; P＜0.007). In 21 patients with PFO, large PFOs were more prevalent in the infratentorial than in the non-infratentorial lesion group. CONCLUSIONS: Infratentorial lesions may be independently associated with PFO in patients with ESUS. The presence of infratentorial lesions could predict the presence of PFO in ESUS cases.

Characteristics and Prognosis of Stroke in Living Donor Renal Transplant Recipients.

AIMS: We aimed to determine the characteristics and vascular outcomes of stroke in renal transplant (RT) recipients and compare them with those in patients on hemodialysis (HD) and those with no renal replacement therapy (RRT). METHODS: In this prospective observational study, 717 patients (mean age, 70.8 years; male, 60.5%) with acute ischemic stroke within one week of onset were consecutively enrolled and followed for one year. The patients were classified into three groups: (1) living donor RT recipients (n=27); (2) patients on maintenance HD before the index stroke (n=39); and (3) those with no history of RRT (n=651). The primary outcome was a composite of major adverse cardiovascular events (MACE). RESULTS: Diabetic nephropathy was the most common reason for RRT in both RT and HD patients. RT patients were more likely to have embolic stroke of undetermined source (33.3%) than others, whereas HD patients more often had cardioembolism (51.3%). No difference was observed in the MACE risk between the patients in RT and non-RRT groups (annual rate, 11.3% vs. 13.1%; log-rank P=0.82; hazard ratio [95% confidence interval], 0.92 [0.29-2.98]). In contrast, HD patients had a greater risk of MACE than those with no RRT (annual rate, 28.2% vs. 13.1%; log-rank P=0.019; hazard ratio [95% confidence interval], 2.24 [1.16-4.3]). CONCLUSIONS: The underlying etiologies of stroke differed in RT and HD patients. The one-year risk of MACE for stroke patients who had received an RT was lower than that for patients undergoing HD and comparable with that of patients with no RRT.

Recurrent Stroke Incidence and Etiology in Patients with Embolic Stroke of Undetermined Source and Other Stroke Subtypes.

AIMS: This study aimed at clarifying the incidence of recurrent stroke and its etiology in patients with embolic stroke of undetermined source (ESUS) and other stroke subtypes in both the acute and chronic periods. METHODS: A total of 645 patients who were admitted with acute ischemic stroke (IS) between March 2015 and August 2019 were enrolled. Among them, 511 patients with ESUS, cardioembolism (CE), large artery atherosclerosis (LAA), or small vessel disease (SVD) were analyzed in this study. After discharge, 391 patients who visited the outpatient clinic were followed up until August 2020. The outcome was stroke recurrence. RESULTS: In the acute admission, recurrence rates were 7.6%, 8.1%, 18.8%, and 2.2% in patients with ESUS, CE, LAA, and SVD, respectively, and there were significant differences between the groups. The subtype of recurrence was almost identical to that of the index stroke. In the outpatient clinic, the annual recurrence rates were 4.4%, 4.3%, 6.0%, and 2.9% in ESUS, CE, LAA, and SVD, respectively, and no difference was observed. Subtypes of recurrence in outpatients with ESUS included ESUS, intracerebral hemorrhage (ICH), and SVD. Patients with ESUS and SVD had a higher risk of ICH during follow-up. CONCLUSIONS: Although the risk of recurrence was comparable between patients with ESUS and CE and intermediate between patients with LAA and SVD, in the acute admission unit, the risk in outpatients was similar among all subtypes. ESUS was the most recurrent stroke subtype in outpatients with ESUS. The risk of hemorrhagic stroke was significant in patients with SVD and ESUS.

Diagnostic Utility of Polymerase Chain Reaction for Paraffin-embedded Sinus Specimens for Rhinocerebral Mucormycosis Complicated by Internal Carotid Artery Thrombosis and Cerebral Infarction.

We herein report a 73-year-old man who experienced cerebral infarction caused by infection with a Mucromycocetes species. A delay in anti-fungal treatment might result in a lethal clinical outcome. We were unable to establish an accurate diagnosis based on histological findings and cerebrospinal fluid culture. Therefore, we performed polymerase chain reaction (PCR) using paraffin-embedded specimens, and based on the findings, successfully started administering anti-fungal treatment. We suggest that PCR using sinus specimens be applied when mucormycosis is suspected as an etiology of cerebral infarction and a confirmative diagnosis cannot be established based on the results of pathological examinations or cerebrospinal fluid culture.

Impaired Endothelial Function in Embolic Stroke of Undetermined Source.

BACKGROUND: Impairment of endothelial function is associated with atherosclerosis and atrial fibrillation, and could underlie several types of ischemic stroke. Embolic stroke of undetermined source (ESUS) recently attracted much attention as the major cause of cryptogenic stroke. This study aimed to clarify the endothelial function of patients with ESUS. METHODS AND RESULTS: Between 2015 September and July 2017 July, we used flow-mediated vasodilation (FMD) test to evaluate vascular endothelial function in 182 patients with any vascular risk factors or a history of cerebrovascular events. The subject group was classified into the No Stroke group and 5 stroke subtype groups, large artery atherosclerosis (LAA), cardiogenic embolism (CE), small vessel disease (SVD), ESUS, and others (Other). Endothelial function was expressed as percentage increase in brachial vessel diameter (%FMD) after the interruption of blood flow with mechanical compression for 5 minutes. Mean FMD in the No stroke, LAA, CE, SVD, ESUS and Other groups were 7.03 ± 2.14%, 5.02 ± 2.75%, 4.97 ± 1.62%, 5.19 ± 2.67%, 3.55 ± 1.42%, and 6.55 ± 3.50%, respectively. After the adjustment for confounding factors, FMD was significantly lower in the ESUS group than in the No stroke, SVD, and Other groups. FMD tended to be lower in the ESUS group than in the LAA and CE groups, but the difference was not significant. CONCLUSIONS: Endothelial function was impaired in patients with ESUS and may underlie its pathophysiology.